Combining Homogeneous Catalysis with Heterogeneous Separation using Tunable Solvent Systems † Vittoria M. Blasucci, ‡,| Zainul A. Husain, ‡,| Ali Z. Fadhel, ‡,| Megan E. Donaldson, ‡,| Eduardo Vyhmeister, ‡,| Pamela Pollet, §,| Charles L. Liotta,* ,‡,§,| and Charles A. Eckert* ,‡,§,| Georgia Institute of Technology, School of Chemical & Biomolecular Engineering, 311 Ferst DriVe, Atlanta, Georgia 30332-0100, Georgia Institute of Technology, School of Chemistry & Biochemistry, 901 Atlantic DriVe, Atlanta, Georgia 30332-0400, and Georgia Institute of Technology, Specialty Separations Center, Atlanta, Georgia 30332-0100 ReceiVed: July 30, 2009; ReVised Manuscript ReceiVed: September 14, 2009 Tunable solvent systems couple homogeneous catalytic reactions to heterogeneous separations, thereby combining multiple unit operations into a single step and subsequently reducing waste generation and improving process economics. In addition, tunable solvents can require less energy than traditional separations, such as distillation. We extend the impact of such solvents by reporting on the application of two previously described carbon dioxide tunable solvent systems: polyethylene glycol (PEG)/organic tunable solvents (POTS) and organic/aqueous tunable solvents (OATS). In particular, we studied: (1) the palladium catalyzed carbon-oxygen coupling of 1-bromo-3,5-dimethylbenzene and o-cresol to potassium hydroxide to produce o-tolyl-3,5-xylyl ether and 1-bromo-3,5-di-tert-butylbenzene to potassium hydroxide to produce 3,5-di-tert-butylphenol in PEG400/1,4-dioxane/water and (2) the rhodium-catalyzed hydroformylation of p-methylstyrene in water/ acetonitrile to form 2-(p-tolyl) propanal. In addition, we introduce a novel tunable solvent system based on a modified OATS where propane replaces carbon dioxide. This represents the first use of propane in a tunable solvent system. 1. Introduction We exploit tunable solvent systems to couple the benefits of both homogeneous and heterogeneous catalysis. Separation is more facile in heterogeneous catalysis, but reactivity and product selectivity suffer and mass transfer limitations may dominate. 1 In the investigated tunable systems, gas, either CO 2 or propane, is added to the homogeneous reaction phase to induce a postreaction phase-split between the polar protic component (water or polyethylene glycol (PEG)) and the relatively nonpolar aprotic component (acetonitrile, dioxane, or tetrahydrofuran), as shown in Figure 1. Operationally, this phase split is easily reversed upon gas depressurization, thereby allowing a solvent switch between homogeneous and heterogeneous and vice versa. Whereas tunable solvents include both supercritical and near- critical fluids, here we focus on those whose properties, such as solvent power and diffusivity, can be gradually adjusted through the use of a pressurized gas, most commonly carbon dioxide (CO 2 ). 2 Several such tunable solvent systems have been published. 3-9 Here we expand the use of these systems with new applications for the pharmaceutical and fine chemical industries, and we characterize a novel propane-based tunable solvent. In designing tunable solvent systems, the applicability of the system to real processes depends strongly on phase equilibria. There is generally a limited region in pressure-temperature- composition space where two liquid phases exist. That region is most useful if it occurs under readily attainable conditions and if it is large. Furthermore, one seeks an area of relatively wide disparity in the compositions of the two liquid phases so that solvent waste is minimized and the solute distribution is as skewed as possible to yield efficient separation. Fluids are selected where specific interactions (hydrogen bonds, Lewis acid/base interactions, etc.) give preferential distributions. Finally, we need to choose fluids that do not interfere with the chemistry of the reaction. Then, such systems may be applied to couple homogeneous reaction to heterogeneous separation for enhanced reaction rates and minimal environmental impact. We report (1) the palladium-catalyzed coupling of 1-bromo- 3,5-dimethylbenzene and o-cresol to potassium hydroxide to produce o-tolyl-3,5-xylyl ether and 1-bromo-3,5-di-tert-butyl- benzene to potassium hydroxide to produce 3,5-di-tert-butylphe- nol in PEG 400/1,4-dioxane/water, (2) the rhodium-catalyzed hydroformylation of p-methylstyrene in water/acetonitrile to form 2-(p-tolyl) propanal, and (3) the phase behavior of a propane-induced tetrahydrofuran (THF)/water tunable solvent system. Although here we describe the first application of PEG- based tunable solvents and propane tunable solvents, organic/ aqueous tunable solvent (OATS) systems, using CO 2 as a switch, have been used for enzyme recycle in biocatalytic reactions 3,4 and for catalyst recycle in the hydroformylation of 1-octene. 9 † Part of the special issue “Green Chemistry in Energy Production Symposium”. * Corresponding author. ‡ Georgia Institute of Technology, School of Chemical & Biomolecular Engineering. | Georgia Institute of Technology, Specialty Separations Center. § Georgia Institute of Technology, School of Chemistry & Biochemistry. Figure 1. Tunable solvent system schematic where L1 is the polar liquid and L2 is the less-polar liquid. J. Phys. Chem. A 2010, 114, 3932–3938 3932 10.1021/jp907325y  2010 American Chemical Society Published on Web 10/09/2009